Pro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice.

Abstract

Acute serum amyloid A (SAA) is an apolipoprotein that mediates pro-inflammatory and pro-atherogenic pathways. SAA-mediated signalling is diverse and includes canonical and acute immunoregulatory pathways in a range of cell types and organs. This study aimed to further elucidate the roles for SAA in the pathogenesis of vascular and renal dysfunction. Two groups of male ApoE-deficient mice were administered SAA (100 µL, 120 µg/mL) or vehicle control (100 µL PBS) and monitored for 4 or 16 weeks after SAA treatment; tissue was harvested for biochemical and histological analyses at each time point. Under these conditions, SAA administration induced crosstalk between NF-κB and Nrf2 transcriptional factors, leading to downstream induction of pro-inflammatory mediators and antioxidant response elements 4 weeks after SAA administration, respectively. SAA treatment stimulated an upregulation of renal IFN-γ with a concomitant increase in renal levels of p38 MAPK and matrix metalloproteinase (MMP) activities, which is linked to tissue fibrosis. In the kidney of SAA-treated mice, the immunolocalisation of inducible nitric oxide synthase (iNOS) was markedly increased, and this was localised to the parietal epithelial cells lining Bowman's space within glomeruli, which led to progressive renal fibrosis. Assessment of aortic root lesion at the study endpoint revealed accelerated atherosclerosis formation; animals treated with SAA also showed evidence of a thinned fibrous cap as judged by diffuse collagen staining. Together, this suggests that SAA elicits early renal dysfunction through promoting the IFN-γ-iNOS-p38 MAPK axis that manifests as the fibrosis of renal tissue and enhanced cardiovascular disease.

• Authors: Antony Gao, Sameesh Gupta, Han Shi, Yuyang Liu, Angie L Schroder, Paul K Witting, Gulfam Ahmad
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 22 (Nov 22 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34830462 (Publication Type: Journal Article)

Chemical References

• Apolipoproteins E
• IFNG protein, mouse
• NF-E2-Related Factor 2
• NF-kappa B
• Nfe2l2 protein, mouse
• Serum Amyloid A Protein
• Interferon-gamma
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• p38 Mitogen-Activated Protein Kinases
• Metalloproteases

Topics

• Animals
• Aorta (metabolism)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (blood, genetics, pathology)
• Humans
• Inflammation (blood, genetics, pathology)
• Interferon-gamma (genetics)
• Kidney Diseases (genetics, pathology)
• Male
• Metalloproteases (genetics)
• Mice
• NF-E2-Related Factor 2 (genetics)
• NF-kappa B (genetics)
• Nitric Oxide Synthase Type II (genetics)
• Serum Amyloid A Protein (genetics)
• Signal Transduction (genetics)
• p38 Mitogen-Activated Protein Kinases (genetics)